Neurofibromatosis type 1 (NF1) is a
neurocutaneous syndrome caused by pathogenic variants in the NF1 gene, encoding a multidomain inhibitor of Ras activity. Thus, NF1 is considered a RASopathy and drugs targeting the RAS/
mitogen-activated protein kinase (MAPK) pathway, such as the MAP
kinase (MEK) 1/2 inhibitor
Selumetinib, are promising therapeutic options to treat NF1-associated
tumors, especially
plexiform neurofibromas and optic way
gliomas. However, surgical treatment is often required for NF1-related cerebrovascular manifestations, such as
moyamoya syndrome (MMS). We report a case of an 8-year-old patient receiving
Selumetinib at the dose of 25 mg/m2 orally 2 times a day as a treatment for many
plexiform neurofibromas. He suffered from two close
strokes and brain MRI revealed a severe cerebral vasculopathy consistent with MMS, with marked
stenosis of both the internal carotid arteries. A two-step surgical revascularization procedure was performed, consisting of a direct by-pass with an encephalo-mio-synangiosis (EMS) followed by encephalo-duro-arterio-synangiosis (EDAS). Surprisingly, despite the surgical technical success, follow-up MRI revealed lack of the expected revascularization.
Selumetinib is a powerful therapeutic option in the treatment of severe NF1-related
tumors. However, our findings suggest that this
drug may interfere with cerebral neovascularization in patients with MMS requiring surgical revascularization. This is supported by the crucial role of the
Vascular-Endothelial Growth Factor (
VEGF), whose signaling pathway involve MAPK, as promoter of the neovascularization. Our observations suggest to adopt an imaging surveillance strategy to prevent unfavorable surgical outcome in patients with NF1-associated MMS receiving
Selumetinib, and that priority should be given to surgical revascularization.